Amino salts of boric acid-aliphatic polyhydroxy carboxylic acid condensation product



Patented Jan. 8, 1952 AMINO SALTS OF BORIC ACID-ALIPHATIC POLYHYDROXY GARBOXYLIC ACID CON- DENSATION PRODUCT David Curtis, New York, N. Y.

No Drawing. Application September 30, 1946,

Serial No. 700,351

11 Claims. (Cl. 260-462) The present invention relates to a new series of amino-organic salts of boric acid in association with aliphatic polyhydroxy carboxylic acids, monobasic and polybasic, and to preparations formed from the same.

It is an object of the present invention to provide a series of new compounds which may combine in one molecular structure a plurality of different therapeutic substances.

It'is another object of the present invention to provide compounds of the character described, possessing enhanced therapeutic values by reason of the increased solubility of such compounds in water and other solvents.

It is also an object of the present invention to provide new therapeutic preparations containing the compounds of the present invention.

It is still another object of the present invention to provide vehicles for the formation therein of the compounds and preparations of the present invention.

It is yet another object of the present invention to devise methods for the preparation of the compounds of the present invention and their components and of the preparations formed therefrom.

It is a further object of the present invention to provide new compounds which, while they retain the-characteristic penetrability of the boric acid, may contain less of the boric acid in proportion to the base present than heretofore found practical, thus reducing in quantity the more orless toxic boric acid.

It is a still further object of the present invention to provide compounds in which the presence of the aliphatic polyhydroxy carboxylic acid in'the molecule, may also, in many instances, confer an antidotal efiect. I

- The acid to which the amino-organic bases are to be linked, to form the salts of the present invention, is, generally speaking, boric acid activated to a greater degree of dissociation than normal through the presence of an aliphatic polyhydroxy carboxylic acid. These aliphatic polyhydroxy carboxylic acids are those having a straight carbon chain containing between at least 5 and 8 carbon atoms in the chain and at least two hydroxyl groupings attached to two adjacent carbon atoms in the chain lying in the same plane, that is, lying on the same side of the carbon atoms.

These acids include, principally, d-gluconlc acid, d-galactonic acid, a-d-gluco heptonic acid, d-gulonic acid, arabonic acid and mucic acid and their lactones, such as the alpha, gamma and delta lactones. Other acids that could be used are d-talonic acid, a-l-rhamno-heptonic acid, l-rhamnonic acid, d-mamonic acid as well as levulose carboxylic acid and other carbohydrate acids capable of activating boric acid to a greater degree of dissociation and activity.

The boric acid itself, in association with a polyhydroxy carboxylic acid becomes more reactive, dissociates in certain liquids, such as 10 -water, for instance, to a greater degree as compared with the boric acid alone, and becomes soluble in certain liquids to an inordinate degree as compared with boric acid itself. The greater solubility and reactivity of this form of boric acid enables it to combine more readily with numerous amino-organic substances of a therapeutic nature, to form valuable preparations. Such salts are also more soluble in certain solvents, are more acid in reaction, which is conductive to a greater degree of freedom from decomposition, and require less of the boric acid in the preparation than would otherwise be the case.

' These salts have the further advantage, in some cases, of combining in the same molecule more than one therapeutic substance, leading to a greater degree of solubility in a desirable solvent like water, and to a more regulated uniformity of action.

It is known that a greater than normal degree of dissociation of boric acid may be secured through the presence of any of several kinds of polyhydroxy substances or mixtures of them. The increased degree of dissociation is attributed to the formation of new ionizable compounds between the boric acid and the polyhydroxy substance.

(J. Boeseken et al. Proc. K. Akad. Wetensch. Amsterdam, 1916, vol. 18, pp. 1647-53; Maganini- A. 1890, p. 1357; 1891, p. 251.)

(Boeseken et al. in Rec. Trav. Chim., 1911, v. 30, pp. 392-406, shows that the two OH groups of such polyhydroxy compounds must be adjacent to each other and in the same plane, on the same side of the carbon atoms to which they are attached, thus permitting the formation of ring combinations with boric aci (Prideau-Zeitsch. Anorg. Chem., 1913, v. 83, pp. 362-68.)

(P. H. Hermans-Z. Anorg. Alg. Chem., v. 142, pp. 83-110 (1925)--b0ric acid readily forms esters with polyhydroxy alcohols, increasing the acidity and conductivity of the solution.)

(J. Boeseken et a1.-Rec. 'Irav. Chim, 1918', v. 37, pp. -183, lists gluconic acid as a polyhydroxy substance in reactivity with boric acid.)

The various polyhydroxy compounds, including the polyhydroXy-carboxylic acids and the salts thereof may activate the boric acid to a different degree of dissociation and reactivity. The different polyhydroxy corboxylic acids themselves and the different salts of the polyhydroxy carboxylic acids may be required in different amounts to activate the same proportion of boric acid, and the same variation of activation may be found in different salts of the same acid.

The boro-polyhydroxy carboxylic acids may be formed by mixing the boric acid and the desired aliphatic polyhydroxy carboxylic acid or the lactone thereof, in preferably equimolar proportions, or in the proportion of two molar equivalents of the acid to one of the boric acid, dissolving the mixed material in a small volume of water, and boiling up the solution. The amount of boric acid that may enter into reaction with the organic acid is considerably greater than would ordinarily dissolve in the volume of water employed, tending to show the formation of a new compound between the reactants. The newly formed, addition product acid may dissolve in some volatile vehicle, such as acetone, in which either one of its constituents has limited or practically no solubility.

The addition product boro-organic acid may also be formed by mixing the boric acid and the organic acid or the lactone thereof in suitable proportion and heating the mix in a suitable glass or porcelain vessel over a low flame hot plate until agglomeration takes place, and heating and mixing the components to a pasty consistency, dissolving the formed compound in a small volume of water and boiling up the solution.

The pasty mass may also be cooled and dissolved in a volatile vehicle, such as acetone or isopropyl alcohol, or other suitable alcohol.

The constituents may also be dissolved in a suitable vehicle by heatin the same under the reflux, if indicated, until combination and solution takes place. The boro-organic acid may then be recovered by removing the volatile vehicle, drying and warming in vacuum to finish off the operation, if desired and indicated.

The formed bore-organic acid may be dissolved after formation, or during the process of formation, in a suitable vehicle and the appropriate amino-organic base dissolved in the same vehicle, or separately, in another vehicle and the solutions brought together, to form the desired combination with the boro-organic acid, by heating and agitation or in the cold, as the case may be.

The formula of the molecule of the boro-organic acid wherein the combination is unlmolecular is probably as follows:

C-OH 111011)? EEHzOH and the reaction'between the section of the diol and the metaboric acid (orthoboric acid less one molecule of water) Boon | HBO: HGOH ni-o Where two moles of the diol are combined with one mole of boric acid, the formula is probably as follows:

Where R stands for an amino-organic base.

While I may use the equimolecular amounts of the organic and boric acids for combination, or a two molar equivalent of the organic acid to one of the boric acid, to which subsequently to attach the appropriate amino-organic compound, I do not confine myself to these particular proportions to form the acid and I may use a considerable amount of each constituent over the other. The predominance of the organic acid over the boric acid leads to the greater and easier reactivity of the latter and for the easier formation of the amino-organic salts of the acid. The predominance of the boric acid, on the other band, also facilitates, to a certain extent, the formation of the desired salt.

In the formation of the bore-organic acids, the lactones of the acids, as well as the acids, may

- be used, such as the delta, gamma, alpha lactones, and the like, utilizing the same methods and vehicles outline above. Other vehicles for theformation of the boro-lactone compounds may be utilized for the solution of the lactones and the boric acid.

Mixtures of acids or lactones of different acids may be used with boric acid for the formation of the boro-organic acid. In addition to the orthoboric acid, other forms of boric acid capable of being activated by the organic acids listed above to a greater degree of activity and dissociation may be used for the formation of the salts of the present invention, suchas borax, metaboric acid, boric acid anhydride, or the like.

The boro-organic acids described above may be linked to one or more organic bases which may be present in an amount to combine with part or with all of the available acidity of the acid compound.

Another method of forming the salts of the presentinvention is by first forming an aminoorganic salt of an aliphatic polyhydorxy carboxylic acid and then linking such salt to boric acid. This may be done by dissolving the salt and boric acid in a suitable solvent, such as water. The amount of water used may be smaller than would be normally required to dissolve the amount of boric acid used. The solution is then stirred and boiled up, under a reflux, if necessary, sufiiciently long to effect solution of the components.

The presence of the amino-organic salt of the organic acid in the solution activates the boric 7:; acid to combine with it either unimolecularly or two molecules of the salt to one of the boric acid, to form a new compound which is of an acid nature and may in turn be linked to another, suitable amino-organic base. The amount of or anic base to be linked to this new acid compound may be in an amount to partially or completely account for the total acidity produced by the boric acid part of the compound.

The solutions may be taken down to dryness to efiect more uniform and complete formation of thesalts of the boro-organic acid compounds, and these may then be redissolved in a suitable vehicle and used when needed; many of the solutions may also be made up in a suitable vehicle, ready for immediate use.

The organic bases that may be used to form the compounds of the present'invention are the amino-organic bases; that is the organic nitrogenous compounds which have an amino or substituted amino grouping in the molecular structure, which amino grouping is capable of combining with an acid.

Among such organic amino compounds are the anaesthetic bases of the type of alkyl, aryl and alkamine esters of amino-aromatic acid.

The alkyl esters of the amino aromatic acids include the alkyl esters of amino-benzoic acid of the para, and other isomeric forms, and the alkyl esters of aminocinnamic acid, as Well as other aromatic acids. Among these are, principally, the following: ethyl-p-amino benzoate, as well as methyl, propyl and butyl (normal and iso) and like esters of p-amino benzoic acid. Also the ethyl, methyl, propyl and butyl and like esters of p-amino-cinnamic acid.

The alkamine esters of amino-aromatic acids include, principally, such esters of amino benzoic acid, amino-cinnamic acid and other aminoaromatic acids, in their para, and other isomeric forms. Among them are procaine, butyn, pentocaine. Others that may be used are dipropyl amino-ethyl-p-amino benzoate, dibutyl aminoethyfl-p-amino benzoate; diethyl amino-propylp-amino benzoate; dipropyl-amino-propyl-pamino benzoate. Also anaesthetic such as nupercaine, eucupin and the like. Likewise, these alkamine esters of" amino-aromatic acids include compoundsin which the esterifying amino alcohol is of the secondary type, as well as those of the usual tertiary type, as, for instance, monoethyl amino ethyl-p-amino benzoate, mono-butyl amino-propyl-p-amino benzoate, and the like.

The organic nitrogenous compounds that may be used to form the compounds of the present invention also include the alkaloids, such as quinine, brucine, and berberine, strychnine.

Another group of organic nitrogenous compounds that are basic substances that can be used to form the salts of the present invention are the vasoconstrictors, including, principally, epinephrine, synephrin-e, neo-synephrine, cobephrine, tyramine, epinine, ephoetonine, and ephedrine. Others that might be used are p-oxyepinephrine, 3-methoxy-4-hydroXy-phenylisopropylamine, b-p -hydroxyphenyl isopropylamine, 3-4-dihydroxyphenyl-a-ethanolamine and allied compounds having vasoconstrictor action.

Another group of nitrogenous bases that may be used to form the salts of the present invention includes the sulfa drugs, such as sulcfanilamide, sulfapyridine, sulfathiazole and sulfadiazine; other acid amides, such as urea, acetamide, methyl acetamide, ethanol urea, methanol urea, and the like; the ethanolamines, such as monoethanol-amine, triethanol-amine, isopropanolamine, and the like, also aniline, p-amino-phenol and para-methylamino-phenol.

In the formation of the salts of the present invention, in cases where the basic substance is suificiently strong or readily soluble in water, enough of it may be added to the acid substance to combine with the total available acidity of the acid substance. Or enough of the base may be added to account for the total acidity due to the polyhydroxy carboxylic acid, and only partially for the acidity of the boric acid. However, under such condition, considerably more of the basic substance may be added to combine with the boric acid portion of the boro-organic compound than is possible with ordinary boric acid. Thus combination of l to 3 molar equivalents of boric acid to one of the base are possible, as compared with the 4 and 5 molar equivalents of boric acid to one of the base, which have been heretofore known.

As an example, procaine salts of boric acid thus activated, may be-produced wherein the procaine is present in an amount of one molar equivalent to 1 or 2 or 3 molar equivalents of boric acid; combinations heretofore unknown. Even when the boric acid in the salt is present in amounts of 4 or 5 and higher molar equivalents to one of the organic base, there are certain advantages derived. For instance, greater acidity with some bases is obtained, leading to greater stability. In other cases, it leads to greater solubility of the basic substance in water or in other solvents. Thus, when some bases are linked to boric acid in proportions of 4 or 5 moles of boric acid to one of base, the solubility ofsuch compound in water or other solvent may be inordinately less than when the like proportion of boric acid and base are linked in the presence of the aliphatic polyhydroxy carboxylic acid.

In cases where the basic substance is a weak base and of limited solubility in water, the combination and solubility may generally be accomplished by using a vehicle in which the basic substance is soluble. Such vehicles include glycerine, propylene glycol, monoethyl ether of propylene glycol, monethyl ether of diethylene glycol and other'ether and ester derivatives of the glycols, and also glycerine ethers.

The solutions of the saltsof the present invention in such vehicles possess the therapeutic or other advantages of such new compounds coupled with the fact that they become miscible with Water or other solvents in which the formed salt would not dissolve to the same extent. Another advantage is that in certain cases a practically water insoluble basic substance may be rendered considerably soluble in this vehicle; a fact heretofore unknown. This is the interesting case, for instance, with the insoluble benzocaine being'rendered soluble to at least 2% concentration in water when linked to a urea-glucono-boric acid compound. The addition of water soluble epinephrine salts or other ,water soluble vasoconstrictonrenders the solution a highly potent anaesthetic.

The salts of the present invention may also be formed by first forming a borate of the particular base and then reacting this borate with a polyhydroxy carboxylic acid of the group enumerated. This may be done, for example, by dissolving or forming procaine monoborate in isopropyl alcohol, in unimolar proportions. be obtained from its solution in isopropyl alcohol by evaporation. It is a white powder giving an This product may 7 alkaline reaction when shaken up with. Water- While it is extremely limited in its solubility in water, such solubility may be greatly increased by the addition of any of the polyhydroxy carboxylic acids named. The addition of delta glucono lactone to the procaine monoborate so lution in isopropyl alcohol and heating, causes a balsamic white precipitate of procaine borogluconate to form.

The formation of organic compounds of the boropolyhydroxy carboxylic lactones of the present invention may also be accomplished by first heating a thorough mixture of the boric acid with the desired lactone in a suitable container over a low heat hot plate to agglomeration and the formation of a paste. The desired organic base or bases may then be stirred in, the heating continued until the base is thoroughly incorporated into the pasty mass, and then allowed to cool. The resulting mass may then be dissolved in a suitable solvent, such as water, or in a volatile solvent, such is iso-propyl alcohol or acetone, and the compound may be obtained therefrom by removing the liquid vehicle. When dissolving such a compound in water or other vehicle, the small amount of the base which may have escaped combination goes into solution on heating and stirring.

The salts of the present invention are, in the main, balsamic, resinous substances which soften on the water bath. Withthe increase of the organic base, especially of the stronger type, the balsamic and resinous nature of the salt is increased. As the boric acid increases in amount, the resulting product tends to become more of a powdery nature.

The acids of the boro-polyhydroxy carboxylic compounds being polybasic, several different organic basic compounds may be linked to such an acid compound, thus enabling the combining of substances of various therapeutic properties in the same molecular structure.

The extent to which the polyhydroxy carboxylic acids of the present invention tend to activate boric acid may be seen from the following conductivity tests:

1. A saturated solution of 6.2 gms. Of HsBOs (0.1 M) in 100 cc. of water failed to cause the passage of a current of 120 volts to allow the wires of a 60 wt. lamp to glow. The addition of as little as 0.178 gm. of delta glucono-lactone (0.001 M) .didallow the solution to conduct such current.

The addition of another 0.178 gm. portion of the lactone caused a greater glow of the lamp even at a greater distance, between the wire ends placed in the solution.

As the amount of the lactone is increased in the solution, the amount of the boric acid becomes dissociated to a greater degree and the conductivity of .the solution increases, the wires of the 60 wt. electric bulb glow with greater brightness.

2. 0.534 gm. of e-glucono lactone (0.003 M) in 100 cc. causes the wires of a 60 wt. lamp barely to glow when the ends of the severed electric wire placed in the solution are at a close distance; the addition of 0.124 gm. of HzBOs 0.002 M) causes the glow to be more intense.

This illustrates that the activation is mutual.

As an example of how a salt of the boro-gluconic acid may indicate the dissociation of the boric acid by the gluconate radicle, cc. of a solution of 2.36 gm. Procaine base-1.78 gm. of delta gluconic acid lactone in 100 cc. of water,

containing 0.0015 M of the salt fails to cause a 6.0 wt. lamp to glow when the 120 volt current is sent through the solution (in 00.), but. when the 15 cc. of the procaine gluconate solution is previously boiled up with 7.5 cc. of a 1.24% of boric acid solution in water and diluted to 100 cc. with water, the current does go through it and lights up a 60 wt. lamp. causing it to glow. This illustrates how an amino organic salt of a polyhydroxy acid of the present invention tends to activate the boric acid with which it combines.

3. d-Galactonic-g-lactone, alpha gluconic lactone, d-gulono lactone g-gluconic lactone, mucic acid were similarly used to activate boric acid in various amounts, all proving that the presence of these polyhydroxy carboxylic acids activate the boric acid in solution to a greater degree of dissociation than normal. The polyhydroXy-carboxylicacid or lactone and boric acid were first boiled up in water before the conductivity test of the solution was taken.

The examples that follow iullustrate the invention, and it is to be understood that the examples are not presented as limitations, for a great number of combinations and compounds may be formed within the spirit of this invention and within the scope of the appended claims. When the alkyl esters of para amino benzoic acid are mentioned it is understood that Orthoform (Methyl metamino-p-oxy-benzoate) is also included and is so claimed.

Example 1.--1.86 gm. of boric acid (0.03 M) and 1.78 gm. of delta-glucono lactone (the equiv. of 1.96 gm. of gluconic acid, 0.01 M) are boiled up in 10 cc. of water; 4.72 gms. of procaine base (0.02 M) are then added to the solution with stirring until the base dissolves, forming procaine bore-gluconate. The solution is diluted to 200 cc. with water and registers an alkaline reaction with litmus.

In this example the boric acid predominates over the gluconic acid; there are 3 molar equivalents of boric acid to one of gluconic acid. There is enough of procaine base present in the above solution, to fully combine with the gluconic acid radicle, and additional procaine base is present in the equivalent of one mole to combine with three of the boric acid, a combination heretofore unknown.

The boric acid-gluconic acid addition compound is of value in being combined with anesthetic substances, since it is known that the gluconates exert an antidotal effect upon the anesthetic substances. (See H. Wastle, Anaesthesiology 2, pp. 661*81, 194=lThe main antidotal effect of the gluconates is probably exerted by the acid radicle of the salt.) It is, therefore, likely that an anesthetic substance linked to boro-gluconic acid would carry its own antidotal power, to a greater or lesser extent, within the molecule.

Example 2.-17.8 gins. of delta-glucono lactone (0.1 M) and 3.1 gins. of boric acid (0.05 M) are dissolved in 10 cc. of water by boiling, forming a soluble compound. The amount of boric acid in this example is entirely too large to go into solution by itself in the volume of water present; the normal solubility of boric acid is only one part in 18 parts or" water in the cold, the formed acid substance remains in solution upon cooling. A compound of gluconic acid and boric acid is evidently formed. Also, when the aqueous solution taken up with 100 cc. of acetone and stirred, it goes completely into solution. Neither the boric acid, nor the gluconic acid present are soluble individually in this combination of water soluble.

boric acid and the polyhydroxy carboxylic acid is The water in this mixture is first abstracted into the acetone and upon stirring, the newly formed ester of the addition product dissolves in the acetone.

Example 3.-8.9 gms. of delta-glucono lactone (0.05 M) and 1.55 gms. of boric acid} (0.025 M) were heated in a hot plate over a low heat until the mass agglomerated and thoroughly softened.

The mass was then taken up with acetone and heated on a water bath until dispersed. 11.80

.gms. of procaine base (0.05 M) were stirred in,

'boric acid addition product.

-Ea:ample 4.8.90 gms. (0.05 M) delta glucono lactone were, dissolved in cc. of water. 1.55 gms. of boric acid (0.025 M) was added on and the solution was boiled up. Then 11.80 gms. of

procaine base (0.05 M) were added to the hot solution and stirred until dissolved. The solution was made up to 500 cc. 0.0183 gm. of epinephrine base was then stirred in and dissolved in the acid solution. The procaine-glucono-borate, which is an acid substance, was here used to dissolve the epinephrine base. This also represents an acid substance having anesthetic properties which is used as a vehicle for the epinephrine base. NaCl and a preservative such as chloretone, or any of the suitable esters of parahydroxy benzoic acid, may be added to the solution; the chloretone in the amount of 0.5% and any of the esters or mixtures thereof in the amount of Anti-oxidants may also be added: such as, sodium bisulphite or acetone sodium bisulphite in the amount of 0.1%, and sodium thiosulphate in the amount of 0.1-0.2 Other vasoconstrictors, such as neo-synephrine, epinine,

cobefrine and others may similarly be incorporated, or added in the form of other salts, such as in the form of the boro-gluconate solutions of these vasoconstrictors, separately prepared. The

- epinephrine may likewise be added to the above solution in the form of a hero-gluconate or as another salt. Vasoconstrictor salts of the present invention may be formedby direct union of the base with the boric acid addition product, or the salts of the vasoconstrictors, as obtainable in the market, may first be appropriately neutralized with a suitable base and the liberated basic vasoconstrictor ma then be linked to the boric acid addition product. 1

These vasoconstrictors may be used singly or in combination with epinephrine in certain amounts, or in combination with each other, in suitable proportions. In particular, valuable combinations of the latter classification may be produced by using two epinephrine substitutes, isomeric with each other, and each lacking in some substituent present in the epinephrine molecule. Each one of such epinephrine substitutes complements the other and together they exert a more favorable vasoconstrictor effect than individually.

I have thus combined 3,4-dihydroxyphenylmethylethylainine (epinine) and L-meta-hydroxyphenylmethylaminoethanol (n e o s y n ephrine). Epinine lacks a hydroxyl group in the chain and neo-synephrine lacks a hydroxyl group in the benzene nucleus, each lacking such a hy- -lecular compound of epinephrine.

' other; the total amount being from one to four parts to ten thousand parts of the final solution, or a higher concentration if indicated or when applied externally, or made up in stock solutions or preparations.

Other amino-organic salts of the present invention may likewise be prepared by first neutralizing the acid component of the salt as obtained in the market with a suitable base, and then redissolving the liberated amino-organic base in the boric acid addition product of the present invention.

Example 5.0.183 gm. of epinephrine base, (0.001 M) is combined with 0.356 gm. (0.002 M) of delta-glucono lactonedissolved in 15 cc. of boiling water. When prepared by double decomposition, as by precipitating out calcium oxalate, epinephrine oxalate with calcium gluconate, unimolecular amounts of each may be used. The epinephrine gluconate solution is acid to litmus paper and indicates a pH of about 4.6 methyl red. 0.062 gm. of boric acid is then dissolved in the solution which is brought to a boil (when cool, its pH is 4.24.3) (bromcresol green) and is then taken down to dryness on the water bath in the presence of a trace of a suitable anti-oxidant. The material then presents a balsamic, resinous substance, softening on the water bath.

Example 6.--1.1716 gms. of Nupercaine (0.00 M) previously dissolved in a volatile vehicle, such as acetone, is combined with 0.98 gm. (0.005 M) of delta-glucone-lactone in water. A slight excess of the lactone may preferably be used. When dissolved and the acetone is driven off, 0.155 gm. (0.0025 M) of boric acid is added and the solution is brought to a boil. 0.04585 gm. of epinephrine base may be stirred in and dissolved in the solution. The solution corresponds to tests for epinephrine.

Example 7.-0.264 gm. of Pantocain base is added to 0.178 gm. of delta-glucono-lactone in 50 cc. of water, and the solution is boiled up to form Pantocain gluconate (dimethyl amino ethylpara-butyl-amino-benzoate-gluconate). The solution has a pH of about 6.3-6.5, bromthymol blue. Dissolving 0.124 gm. of boric acid in the solution and bringing it to a boil forms Pantocain borogluconate. The solution when cooled shows a pH of about 4.4 methyl red. 0.04575 gm. of epinephrine base may be stirred into the solution wherein it dissolves readily, raising the pH to about 6.0 methyl red. The proportions of the composition are 0.001 molar amount of Pantocain gluconate to 0.002 molar amount of boric acid and 0.00025 molar concentration of epinephrine as base. This solution may be added to a stronger concentration of procaine gluconate or other procaine salt, or other anesthetic salt or in a higher concentration by itself may be used as a mild surface anesthetic. The proper amount of epinephrine base may be taken into consideration when the solution is diluted for use or by mixing it with a suitable amount of'Pantocain gluconate or other anesthetic salt in solution. Butyn boro-gluconate may be similarly prepared; or the salt of butyn as obtainable in the market may first be treated with a suitable alkaline substance to precipitate the base, which may then be redissolved in a boro-gluconic acid compound.

Example 7a.-2.36 gms. of procaine base and 2.10 gm. of mucic acid (0.01 M) may be boiled up and combined in about 100 cc. of water. The

acid (0.04 M) are stirred in and the solution is boiled up again. It then registers a pH of about 5.6-5.3 Methyl Red. 0.065 gm. of epinephrine base, or other vasoconstrictor may then be dissolved in the solution. base may be stirred into the solution with the addition of 25-50 cc. of carbitol,-or propylene 1.65 gm. of benzocain glycol. 1

Example 7b.-5.20 gms. of alpha glucoheptonic lactone (0.025 M) are boiled up with 1.55 gm. of boric acid (0.025 M) in about 65 cc. of water. 5.9 gms. of procainebase are then stirred in until dissolved. The soln. registers a pH of about 5.2-5.4 Methyl Red. Taken down to dryness from an acetone solution a resinuous compound is obtained.

d-Gulono-gamma lactone; d-galactono-gamma l'actone may similarly be made to activate boric acid to form an acid addition product, which may then be linked to procaine, or any other suitable amino-organic base to form a salt of the boric addition product.

Example 8.-8.9 gms. of delta-glucono lactone (0.05 M) and 3.1 gms. of boric acid (0.05 M) were heated on a hot plate until the mass agglomerated and softened to a paste. It was then dissolved in 5 cc. of water and brought to a boil. The lactone picks up some water in this solution, forming gluconic acid. 8.25 gms. of benzocain (0.05 M) were stirred in and heated until a clear solution was obtained. This solution could be mixed with ethyl glycerine, propylene glycol, or other derivatives of glycol, to a volume of 100 cc. The formation of mono-boro-gluconic acid may be accomplished by boiling the components in about 5 cc. of water. It may then be diluted with and dissolved in propylene glycol, or other suitable solvent, and the benzocain base may then be stirred in and heated until solution has been accomplished. This example illustrates the formation of benzocain mono-boro-gluconate, combining the benzocain in unimolar proportion to the unimolar boro-gluconic acid, or glucono-boric acid.

Example 9.-The same as in the preceding example, using only 1.55 gm. of boric acid (0.025 M) to 8.9 gms. of. delta-glucono lactone (0.05 M) and heating in a glass container over a hot plate also secures agglomeration and softening of the mass to a pasty consistency. The water evolved in the condensation reaction combines with the lactone, forming gluconic acid. The mass is then dissolved in 5 cc. of water, brought to a boil and 8.25 gms. of benzocain (0.05 .1) are stirred in and heated to a clear solution which upon cooling sufficiently is then taken up with 100 cc. acetone and allowed to stand until it becomes completely miscible with the acetone, and may then be used for impregnating gauze bandages. The acetone is then allowed to evaporate, leaving the benzocain di-glucono-borate incorporated in the gauze bandage. Such an acetone solution may also be mixed with glycerine, propylene glycol, ethylglycerine, carbitol and the like.

This is an illustration of linking the base ben- Zocain to di-glucono boric acid addition product, one molar equivalent of benzocain to one molar equivalent of di-glucono boric acid addition compound.

Example 10.-8.9 gms. of delta-glucono-lactone (0.05 M) were mixed with 1.55 gms. of boric acid (0.025 M) and the mixture was heated in a glass beaker on a hot plate until agglomeration and softening to a paste took place. 11.80 gms. of procaine base (0.05 M) were then stirred in and heated until the base was incorporated into the di-glucono-boric acid. A resinous mass was obtained. When taken up in warm water dispersion took place,. and the material soon went into solution. Any uncombined procaine base in the solid reacted easily and went into solution upon warming. The solution was acid in reaction.

Example 11.-8.9 gms. of delta-glucono-lactone (0.05 M) were heated up with 1.55 gms. of boric acid (0.025 M) and taken up with 5 cc. of water and dissolved therein by boiling. The solution was diluted to cc. with acetone. Upon stirring and allowing to stand, the di-glucono boric acid went into solution.

4.475 gms. of propyl-para-amino benzoate (0.025 M) were then dissolved in the above acetone solution. Solution took place easily. Upon evaporating the acetone a White mass was obtained, softening easily on the steam bath and dissolving in glycerine or propylene glycol upon heating.

This is an example of forming Propoesin diglucono-borate, using two molar equivalents of the acid addition product to one molar equivalent of Propoesin.

Example 12.--8.9 gms. of delta-glucono lactone (0.05 M) plus 3.10 gms. of boric acid (0.05M) were heated in a glass beaker over a hot plate to agglomeration and to a pasty mass, which was then taken up with 5 cc. of water, boiled up and the solution diluted with acetone to 100 cc. The pasty material may also dissolve in acetone without the addition of water. The pasty material is heated in the acetone at the boiling point of acetone until solution takes place.

3.0 gms. of urea (0.05 M) were then stirred into the above solution and soon dissolved. 2.0 gms. of benzocain were then added on and solution took place at once. The solution was taken down to dryness and a resinous substance was obtained.

Example 13.-To prepare a benzocain salt of urea-glucono-borate in an aqueous solution the following may be done: 17.8 gms. of delta-glucono lactone (0.1 M) and 6.0 gms. of urea (0.1 M) are dissolved and boiled up in about '75 cc. of water; 3.1 gms. of boric acid (0.05 M) are then stirred in and the whole is boiled up. Between l.65-2.475 gms. (0.01 to 0.015 M) of benzocain may then be stirred into the hot solution until the benzocain dissolves and the solution is then made up to 100 cc. with water. A very potent anesthetic is obtained. Epinephrine or other 'vasoconstrictor and antioxidant salts may be added to this solution.

This is an illustration how the practically insoluble benzocain may be incorporated into solution in water without the addition of any other solvent whatever.

It is also an example of how an amino organic compound of gluconic acid is first formed (urea gluconate), followed by the formation of an acid compound by boiling the urea-gluconate with boric acid, which becomes dissociated to a much greater degree than normal. A salt may then form with this acid, namely. benzocain-urea-boro gluoonate. The base is benzocain an'd the'acid is urea-boro 'gluconate. Instead of benzocain another suitable base may be used.

The acid substance in the preceding example is a two molar equivalent of urea gluconate to one molar equivalent of boric acid. .Even the benzocain in this case may be incorporated into the compound in a proportion of more than one mole to five moles of boric acid, forming a compound which is water soluble. A water soluble benzocain in combination with boric acid alone, even though the latter be present in proportion of more than five molar equivalents to one of benzocain, has heretofore been unknown.

In Example 13, in addition to 1.65 gm. of benzocain, 1.72 gm. of sulfanilamidemay be stirred in and dissolved in the hot solution of the ureaboro gluconate. This solution may also contain an excess of boric acid, such as 6-7%, a saturated solution of boric acid, as when such a solution is to be applied to the skin, instead of a solution of ordinary boric acid, used by itself. Instead of urea, another amide, such as acetamide, methyl acetamide and the like, may be used. 1.77 gm. of acetamide 0.03 M) may be used.

Example 14.- 1.80 gm. of urea (0.03 M) was dissolved in water with 5.34 gm. of gamma-gluconic acid lactone (0.03 M) and boiled up in a volume of about 75 cc. of water; 1.86 gm. of boric acid (0.03 M) were then stirred in and the solution was boiled up again. 1.72 gm. of sulfanilamide (0.01 M) was then stirred in and solution took place easily. The solution was then made up to 100 cc. with water. This represents a trimolar equivalent combination of urea-mono glucono borate, which is an acid substance, combined with mono molar equivalent amount of sulfanilamide. The sulfanilamide under these conditions becomes more highly soluble in water than ordinary sulfanilamide.

5.34. gms. of delta-glucono lactone dissolved in 100 cc. of water and boiled up with 1.72 'gm; of sulfanilamide causes the latter to go into solu tion; however, precipitation soon takes place.

The Example 14 represents an important combination of sulfanilamide-urea product; since it is known that such combinations show a greater activity towards ordinary bacterial strains and the toxic effects of sulfanilamide are also lessened. Such compounds also possess bacteriostatic activity in the presence of the sulfonamide inhibitor compound, para-amino-benzoic acid. (W. K. Wallenstein, in Nature, May 22, 1943,pp. 586-587) and (Tenenberg at al. in Proc. Soc. Expt. Biol. Med. 51,247, (1942).

It may be deduced that an anesthetic of the group of alkyl and alkamine esters of para-amino benzoic acid may be used in connection with such a urea-glucono boro sulfanilamide combination.

Accordingly, at least 0.5 gm. of benzocain may be stirred into the solution of the preceding example, following the formation of the urea-boro glucono-sulfanilamide preparation, boiling up the solution to dissolve the benzocain.

Example 15.-1.65 gm. of ephedrine (0.01 M) was dissolved in 75 cc. of water and boiled up first with 1.78 gm. of delta-glucono lactone (0.01 M), forming ephedrine gluconate. 1.24 gm. of boric acid (0.02 M) were then added and the solution was boiled up again, forming ephedrine di-boro gluconate, which is an acid substance. 2.36 gm. of procaine base (0.01 M) was then stirred in, and solution soon took place. The solution was alkaline to litmus. This is an example of using one I proportion to an amino organic base.

molecular excess of boric acid in forming the acid substance ephedrine boro-gluconate. It is also an example of how one molar equivalent of procaine base may be made to combine with only a two molar equivalent of boric acid, as present in the ephedrine di-boro gluconate, instead of requiring a four or five molar equivalent of boric acid to one of procaine as only known heretofore.

When procaine base is linked to boric acid in the equivalent proportion of one mole to five moles of boric acid, in the presence of equivalent one mole of gluconic acid, the formation takes place easily in hot water, the reaction of the solution being acid, and therefore more stable than the (1:5) alkaline procaine borate known heretofore.

Example 16.--1.86 gms. of boric acid (0.03 M) may be used to 1.78 gm. of delta-glucono lactone (0.1 M), dissolving the components in hot water, and then adding 2.36 gm. of procaine base (0.01 M) and dissolving in the solution to form a combination of one molar equivalent of procaine base to three molar equivalents of boric acid, a combination heretofore unknown.

Example 17.6 gm. of acetamide (0.1 M) and 17.8 gms. of delta-glucono lactone (0.1 M) were dissolved in 50 cc. of water and the solution was boiled up with 6.2 gms. of boric acid (0.1 M), forming acetamide glucono boric acid. 12.3 gms. of para-methylamino-phenol (0.1 M) (Metol) were then added to the solution and boiled up, forming the Metol salt of the acid. This salt has a greater solubility in water than the correspending Metol sulphate.

The sulphate salt of para-methylamino-phenol may be used with sodiumbicarbonate to set the base free prior to combining it with the acetamide-glucono-boric acid, in the amount of 17.4 gms. of the sulphate salt to 9.0 gms. of sodium bicarbonate.

This is an example of the formation of aceta mide-glucono-boric acid in equimolar proportions and of the linking of this acid in an equimolar The base, Metol, being weak, the solution is acid in reaction and is thus conducive to greater stability of the salt.

Example 18.--8.9 gms. of delta-glucono lactone (0.05 M) and 3.10 gms. oi boric acid (0.05 M) were mixed in a beaker and heated over a low flame hot plate to agglomeration, softening with the formation of a pasty mass. It was then taken up with about 75 cc. of acetone and heated on a water bath until the boro-glucono compound was dissolved.

This illustrates the formation of a boroglucono compound in acetone (iso-propyl alcohol can also be used under these conditions), since neither one of the constituents in the re spective amounts used are soluble to that extent in acetone by themselves. Procaine base in the amount of 11.8 gms. (0.05 M) were then stirred in, with the formation of a silky appearing balsamic substance. Upon driving off the volatile vehicle, a resinous material was obtained, the product softening on a water bath and dissolving in water on warming.

This illustrates the easy formation of a procaine boro-gluconate compound in acetone as compared with a formation of the regular 1:5 procaine borate, since the boric acid is only soluble in acetone in a moderate degree, thus requiring a larger volume of acetone when the regular 1:5 procaine borate is prepared. An-

propoesin.

Emcmple 19.S.9 gms. gamma-glucono lactone (0.05 M) and 3.1 gms. of boric acid (0.05 M) were heated in a glass beaker to a pasty consistency; 8.25 gms. of benzocaine (0.05 M) were stirred in and heated until incorporated into the paste. The mass presented a white slightly amber colored resinous solid, which could be dissolved in about 5-7 cc. of water by heating. The solution was then mixed with 50 cc. of acetone, or other suitable liquids, and the solution was used for gauze impregnation.

Example 20.4.45 gms. of delta-glucono lactone (0.025 M) (0.025 M) were heated to a pasty consistency. 8 gms. of procaine were then incorporated into the pasty mass by heating; the product presented a slightly gray resinous material, which could be softened on a water bath. 2 gms. of this material dissolved in 50 cc. of water on warming registered a pH of about 6.7-6.8 Bromthymol Blue.

4.45 gms. of delta-glucono lactone (0.025 M) and 1.55 gins. of boric acid (0.025 M) were dissolved in 100 cc. of water by boiling. 8.0 gms. of procaine base were added on and stirred until solution took place. The solution registered a pH of about 6.7-6.8 Bromthymol Blue. The addition of 0.5 gm. of delta-glucono lactone brings the pH of this solution down to about 5.4 Methyl Red.

Elrample 21.-l1.8 gms. of procaine base (0.05 M) and 3.1 gms. of boric acid (0.05 M) were dissolved in about '75 cc. of iso-propyl alcohol by boiling on a water bath. When the solution was taken down to dryness, substantially 14 'gms. of procaine mono-borate were recovered. This was a white, brittle powder of a probable composition of R.HBO2 (R standing for procaine), indicating the loss of one mole of water by the boric acid used originally.

2.8 gins. of the above procaine mono-borate (0.01 M) were dissolved in about 50 cc. of isopropyl alcohol, and 1.78 gms. of delta-glucono lactone (0.01 M) was added to the solution, and the solution was boiled on a water bath, forming a precipitate of what was evidently procaine mono-borate gluconate.

This illustrates the formation of an amino organic borate which could be converted into a boro-gluconate of the same base, the amino organic borate in this particular case being a unimolar combination of procaine base and boric acid.

Example 22.3.1 gms. of boric acid (0.05 M) and 8.9 gms. of delta-glucono lactone (0.05 M) were dissolved in iso-propyl alcohol and acetone, in about 100 cc., in equal volumes. 8.25 gms. of benzocaine were then stirred into the solution and the volatile vehicle was driven off. As the benzocaine mono-boro-gluconate solution became more concentrated, a more and more viscous and amber colored mass was obtained, re sulting in a clear, transparent, amber-colored resinous, highly adhesive material upon evaporation of the volatile vehicle.

Example 23.-As an illustration of having two different amino organic salts of gluconic acid activate one molar equivalent of boric acid,

and 1.55 gms. of boric acid 1%) and then linking a third base to the boric acid addition product thus obtained, the following may be cited:

8.9 gms. of delta-glucono lactone (0.05 M) were boiled up with 1.5 gms. urea (0.025 M) and with 4.125 gms. ephedrine (0.025 M). The solution was then boiled up with 3.1 gms. of boric acid (0.05 M); 2.0875 gms. of orthoform (0.0125 M) was then added on and stirred into the solution. The orthoiorm dissolved easily. Urea and ephedrine were thus linked to borogluconic acid, and a third base, orthoform, was then linked to the acid. Instead of orthoform, procaine, or another suitable base, could be used in the example.

Several methods for the preparation of the boric acid-polyhydroxy-carboxylic acid addition compounds were illustrated; The preparation of a particular addition compound will depend upon the pol yhydroxy-carboxylic acid. The. selection of a particular method for the preparation of a salt of the boric acid addition product will depend upon the amino organic base of the particular salt, and upon the polyhydroxycarboxylic acid component of the boric acid addition product, and upon the vehicle in Which the-formation of the salt is to be conducted.

I claim:

1. A salt formed of an amino-aromatic base from the group consisting of alkyl and alkamine esters of an amino-aromatic acid with an addition product of boric acid with an aliphatic, mono-basic, non-substituted polyhydroxy carboXylic acid selected from the group consisting of gluconic acid, galactonic acid, gluco-heptonic acid, gulonic acid, arabonic acid, talonic acid, rharnno-heptonic acid, rhamnonic acid, mannonic aid and levulose-carboxylic acid; said polyhydroXy-carboxylic acid being present in the addition product in the proportion of at least one molar equivalent to one of boric acid.

2. A salt as in claim 1, said boric acid being present in the addition product in the proportion of .at least one equivalent to one of the polyhydroxy carboxylic acid.

3. A salt formed of benzocaine base with an addition product of boric acid and levulose-carboxylic acid; said levulose-carboxylic acid being present in the addition product in the proportion of at least one equivalent to one of boric acid.

4. A salt formed of benzocaine base with an addition product of boric acid and levulose-carboxylic acid; said boric acid being present in the addition product in the proportion of at least one molar equivalent to one of levulose-carboxylic acid.

5. The process of forming a salt of claim 1, which comprises the steps of first forming an addition product of boric acid with an aliphatic, mono-basic, non-substituted polyhydroXy-carboxylic acid-lactone by heating a mixture of the same into a pasty consistency, dissolving the paste in iso-propyl alcohol and dissolving in the same solution the amino-organic base, and removing 1 the solvent vehicle.

6. The process of forming an addition product of boric acid with an aliphatic, mono-basic, nonsubstituted polyhydroxy-carboxylic acid lactone, comprising the steps of heating a mixture of the same into a pasty consistency. dissolving the paste in a volatile vehicle, and removing the solvent vehicle.

'7. The process of forming an addition product of boric acid with an aliphatic, mono-basic, nonsubstituted'polyhydroxy-carboxylic acid lactone.

17 comprising the steps of heating a mixture of the same into a pasty consistency, and dissolving the paste in a volatile vehicle.

8. As in claim 6 in which the volatile vehicle is iso-propyl alcohol.

9. The process of forming an addition product of boric acid with an aliphatic, mono-basic, nonsubstituted polyhydroxy-carboxylic acid lactone, comprising the steps of heating a mixture of the same in a volatile vehicle.

10. The same as in claim 9, in which the volatile vehicle is acetone.

11. The same as in claim 9, in which the volatile vehicle is iso-propyl-alcohol.

DAVID CURTIS.

REFERENCES CITED The following references are of record in the file of this patent:

Number Boesekin et 2.1., Rec. 1 165-178 (1918).

18 UNITED STATES PATENTS Name Date Austin July 9, 1935 Johnson May 19, 1936 Piggott Aug. 25, 1936 Katzman et al 1- Oct. 31, 1939 Curtis July 23, 1940 Katz i Oct. 1, 1940 Curtis Mar. 25, 1941 Curtis May 24, 1942 OTHER REFERENCES Trav. Chim, vol. 37. pp. 

1. A SALT FORMED OF AN AMINO-AROMATIC BASE FROM THE GROUP CONSISTING OF ALKYL AND ALKAMINE ESTERS OF AN AMINO-AROMATIC ACID WITH AN ADDITION PRODUCT OF BORIC ACID WITH AN ALIPHATIC, MONO-BASIC, NON-SUBSTITUTED POLYHYDROXY CARBOXYLIC ACID SELECTED FROM THE GROUP CONSISTING OF GLUCONIC ACID, GALACTONIC ACID, GLUCO-HEPTONIC ACID, GULONIC ACID, ARABONIC ACID, TALONIC ACID, RHAMNO-HEPTONIC ACID, RHAMNONIC ACID, MANNONIC ACID AND LEVULSO-CARBOXYLIC ACID; SAID POLYHYDROXY-CARBOXYLIC ACID BEING PRESENT IN THE ADDITION PRODUCT IN THE PROPORTION OF AT LEAST ONE MOLAR EQUIVALENT TO ONE OF BORIC ACID. 